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Glycogen debranching enzyme (AGL) is a novel regulator of non-small cell lung cancer growth.

ABSTRACT: Glycogen debranching enzyme (AGL) and Glycogen phosphorylase (PYG) are responsible for glycogen breakdown. We have earlier shown that AGL is a regulator of bladder tumor growth. Here we investigate the role of AGL in non-small cell lung cancers (NSCLC). Short hairpin RNA (shRNA) driven knockdown of AGL resulted in increased anchorage independent and xenograft growth of NSCLC cells. We further establish that an increase in hyaluronic acid (HA) synthesis driven by Hyaluronic Acid Synthase 2 (HAS2) is critical for anchorage independent growth of NSCLC cells with AGL loss. Using gene knockdown approach against HAS2 and by using 4-methylumbelliferone (4MU), an inhibitor of HA synthesis, we show that HA synthesis is critical for growth of NSCLC cells that have lost AGL. We further show NSCLC cells without AGL expression are dependent on RHAMM for HA signaling and growth. Analysis of NSCLC patient datasets established that patients with low AGL/high HAS2 or low AGL/high RHAMM mRNA expression have poor overall survival compared to patients with high AGL/low HAS2 or high AGL/low RHAMM expression. We show for the first time that loss of AGL promotes anchorage independent growth of NSCLC cells. We further show that HAS2 driven HA synthesis and signaling via RHAMM is critical in regulating growth of these cancer cells with AGL loss. Further patients presenting with low AGL and HAS2 or RHAMM over expressing tumors might present the ideal cohort who would respond to inhibitors of HA synthesis and signaling.

SUBMITTER: Richmond CS

PROVIDER: S-EPMC5908281 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Glycogen debranching enzyme (AGL) is a novel regulator of non-small cell lung cancer growth.

Richmond Craig S CS Oldenburg Darby D Dancik Garrett G Meier David R DR Weinhaus Benjamin B Theodorescu Dan D Guin Sunny S

Oncotarget 20180330 24

Glycogen debranching enzyme (AGL) and Glycogen phosphorylase (PYG) are responsible for glycogen breakdown. We have earlier shown that AGL is a regulator of bladder tumor growth. Here we investigate the role of AGL in non-small cell lung cancers (NSCLC). Short hairpin RNA (shRNA) driven knockdown of AGL resulted in increased anchorage independent and xenograft growth of NSCLC cells. We further establish that an increase in hyaluronic acid (HA) synthesis driven by Hyaluronic Acid Synthase 2 (HAS2) ...[more]

PMID: 29682180

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Project description:BackgroundBranched polymers of glucose are universally used for energy storage in cells, taking the form of glycogen in animals, fungi, Bacteria, and Archaea, and of amylopectin in plants. Some enzymes involved in glycogen and amylopectin metabolism are similarly conserved in all forms of life, but some, interestingly, are not. In this paper we focus on the phylogeny of glycogen branching and debranching enzymes, respectively involved in introducing and removing of the α(1-6) bonds in glucose polymers, bonds that provide the unique branching structure to glucose polymers.ResultsWe performed a large-scale phylogenomic analysis of branching and debranching enzymes in over 400 completely sequenced genomes, including more than 200 from eukaryotes. We show that branching and debranching enzymes can be found in all kingdoms of life, including all major groups of eukaryotes, and thus were likely to have been present in the last universal common ancestor (LUCA) but have been lost in seemingly random fashion in numerous single-celled eukaryotes. We also show how animal branching and debranching enzymes evolved from their LUCA ancestors by acquiring additional domains. Furthermore, we show that enzymes commonly perceived as orthologous, such as human branching enzyme GBE1 and E. coli branching enzyme GlgB, are in fact related by a gene duplication and consequently paralogous.ConclusionsDespite being usually associated with animal liver glycogen and plant starch, energy storage in the form of branched glucose polymers is clearly an ancient process and has probably been present in the last universal common ancestor of all present life. The evolution of the enzymes enabling this form of energy storage is more complex than previously thought and illustrates the need for explicit phylogenomic analysis in the study of even seemingly "simple" metabolic enzymes. Patterns of conservation in the evolution of the glycogen/starch branching and debranching enzymes hint at some as yet unknown mechanisms, as mutations disrupting these patterns lead to a variety of genetic diseases in humans and other mammals.

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Glycogen debranching enzyme (AGL) is a novel regulator of non-small cell lung cancer growth.

Publications

Glycogen debranching enzyme (AGL) is a novel regulator of non-small cell lung cancer growth.

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